CN102947441A - Cellular constituents from bacteroides, compositions thereof, and therapeutic methods employing bacteroides or cellular constituents thereof - Google Patents

Abstract

A cellular constituent is lysed from, produced by and/or isolated from one or more bacteria from the genus Bacteroides, and the cellular constituent, a derivative thereof, and/or one or more bacteria from the genus Bacteroides, or a modified form thereof, is employed in compositions and methods for modulating an inflammatory response.; Such methods include methods of treating, delaying the onset of, or reducing the symptoms of one or more inflammatory conditions/diseases, including corporal or gastrointestinal inflammation, for example, Irritable Bowel Syndrome, Crohn's Disease, or colitis, and/or associated diseases such diabetes, asthma, multiple sclerosis, cancer, rheumatoid arthritis, gingivitis, atopic diseases, for example, hay fever, food allergies, eczema, rhinitis, dermatitis, conjunctivitis, atopic syndrome and keratosis pelaris, ocular inflammatory disease, strokes, cardiovascular disease, depression, atherosclerosis and hypertension, and comprise administering a composition comprising one or more natural and/or modified bacteria of the genus Bacteroides, and/or a cellular constituent lysed from, produced by, or isolated from one or more natural and/or modified bacteria from the genus Bacteroides, or a derivative thereof.

Description

Cellular components from Bacteroides, compositions thereof and methods of treatment using Bacteroides or cellular components thereof

field of invention

The present invention relates to cellular components and derivatives thereof derived from bacteria of the genus Bacteroides, compositions comprising such cellular components or derivatives thereof and the use of such cellular components or derivatives thereof or derived from Bacteroides bacterium, or a genetically modified form thereof, including methods for treating, delaying the onset or reducing the symptoms of one or more inflammatory conditions/diseases involving the body or the gastrointestinal tract Inflammation and/or related diseases such as diabetes, asthma, multiple sclerosis, cancer, rheumatoid arthritis, gingivitis, atopy, ocular inflammatory disease, stroke, cardiovascular disease, depression, atherosclerosis and hypertension blood pressure.

Background of the invention

The health of the human host depends on the ability of the immune system to recognize and adapt to a myriad of foreign and self molecules and to respond in an appropriate manner to ensure maintenance of host homeostasis. Several recent studies have shown that the gastrointestinal microbiota plays an important role in the proper functioning of the immune system and in preventing the onset of inflammatory responses that subsequently contribute to disease states such as inflammatory bowel disease, type 2 diabetes (TD2) and cardiovascular disease (CVD). Abdominal obesity, with its subsequent increased fat deposition within omental adipocytes, has been associated with inflammatory processes and an increased risk of developing a number of diseases. It is commonly understood that the omentum is the most prolific endocrine organ within the human host. As adipocyte mass increases, secretion of cytokines such as interleukins 1 and 6 and tumor necrosis factor α (TNF-α) also increases, while adiponectin, a molecular insulin sensitizer, decreases (Kojima, S .Et al., 2005.Levels of the adipocyte-derived plasma protein, adiponectin, have a close relationship with atheroma (the level of adipocyte-derived plasma protein - adiponectin - has a close relationship with atheroma).Thromb.Res.115:483 ; Ryo, M. et al., 2004. Adiponectin as a biomarker of metabolic syndrome (Adiponectin as a biomarker of metabolic syndrome). Circ. J. 68:975). This in turn disturbs hepatic metabolism, causes hyperlipidemia and promotes proliferation of vegetative vessels within the arterial media, macrophage migration and subsequent damage to the circulatory system due to inflammatory processes, thereby increasing arterial injury (Corti, R. et al., 2004. Evolving concepts in the triad of atherosclerosis, inflammation and thrombosis (evolutionary concepts among atherosclerosis, inflammation and thrombosis). J.Thromb.Thromolysis.17:35). Evidence suggests that the gut microbiota plays a role during inflammation by stimulating the immune system's cytokine/chemokine response and can significantly influence the initiation and promotion of many physiological processes involved in disease development. Modulation of the bacterial system can help improve or reduce the symptoms/severity of such inflammation-related disease processes including CVD, diabetes, inflammatory bowel disease, hypertension, asthma, multiple sclerosis and cancer (Skurk, T. and H. Hauner, 2004.Obesity and impairedfibrinolysis:role of adipose production of plasminogen activator-1 (obesity and impaired fibrinolysis: the role of adipose production of plasminogen activator-1).Int.J.Relat.Metab .Disord.28:1357; Corti, R. et al., 2004. Evolving concepts in the triad ofatherosclerosis, inflammation and thrombosis (the evolutionary concept in the three of atherosclerosis, inflammation and thrombosis). J.Thromb.Thromolysis. 17:35). In addition, it has recently been proposed that the genome of the microbial population is critical in maintaining the overall health of the host, and that the overall host genome is itself insufficient in supporting the repertoire of functions required to maintain host homeostasis (Zaneveld, J. et al., 2008. Host-bacterial co-evolution and the search for new drug targets (host-bacterial co-evolution and exploration of new drug targets). Curr.Opin.Chem.Biol.12:109).

Type 2 diabetes (T2D) is often associated with obesity and metabolic syndrome (Hu, F.B. et al., 2001. Diet, Lifestyle and the risk of type 2 diabetes mellitus in women (Diet, lifestyle and risk of type 2 diabetes in women) （ Definition, diagnosis and classification of diabetes and its complications, Part 1: Diagnosis and classification of diabetes, WHO expert interim report). Diab.Med.15:539). Although the exact mechanism is not fully elucidated, the consensus is that chronic, low-grade obesity-induced inflammation (e.g. through activation of protein kinases such as IkB kinase (IKK) and Jun kinase (JNK)) is an important factor (Hotamisligil, G.S. 2006. Inflammation and metabolic disorders (inflammation and metabolic disorders). Nature.444:860; Shoelson, S.E. et al., 2006.Inflammation and insulin resistance (inflammation and insulin resistance). J.Clin.Invest.116:1793; White, C.R.2003.Insulin Signaling in health and disease (insulin signaling under health and disease). Science.302:1710; Solinas, G.C. et al., 2007. JNK1 in hematopoieticllyderived cells contributes to diet-induced inflammation and insulin resistance withoutaffecting obesity (in hematopoietic derived cells JNK1 contributes to diet-induced inflammation and insulin resistance without affecting obesity). Cell Metabol. 6:386). Pathogen-associated molecular patterns (PAMPs) from multiple bacterial genera and species are known to elicit IKK inflammatory responses (Doyle, S.L. and L.A. O'Neill, 2006. Toll-like receptors: from the discovery of NF-κB to new insights into transcriptional regulations in innate immunity (Toll-like receptors: from the discovery of NF-κB to a new understanding of transcriptional regulation in innate immunity). Biochem.Pharmacol.72(9):1102).

Irritable bowel syndrome (IBD) is associated with a shift from a regulated intestinal immune response to one characterized by unfettered immunological cell activity and proinflammatory cytokine production (De Winter, H. et al, 1999. Mucosal immunity and inf1ammation (mucosal immunity and inflammation). II. Theyyin and yang of T cells in intestinal inflammation: pathogenic and protective rolesin a mouse colitis model (yin and yang of T cells in intestinal inflammation: mouse Pathogenic and protective effects in colitis model). Am J Physiol.276:G1317; Simpson, S.J. et al., 2000. Pathways of T cell pathology in models of chronic intestinal inflammation (T cell Pathway of disease). Int.Rev.Immunol.19:1; Elson, C.O. et al., 2007. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice (monoclonal anti-interleukin 23 reverses T cell-mediated Active colitis in a mouse model). Gastroenterology 132:2359). IBD includes Crohn's disease and ulcerative colitis, both of which have been associated with the GI microbiota (Podolsky, D.K., 2002. The current future understanding of inflammatory bowel disease (current future understanding of inflammatory bowel disease). BestPract.Res .Clin.Gastroenterol.16:933; Shanahan,F.2002.Crohn's Disease (Crohn's disease).Lancet.359:62-69;Targan,S.R. and L.C.Karp.2005.Defects in mucosalimmunity leading to ulcerative colitis (mucosal Defects in immunity lead to ulcerative colitis). Immunol. Rev. 206:296). Experimental evidence also showed that transfer of colitis-causing microbial populations to wild-type mice was sufficient to induce experimental ulcerative colitis (Garrett, W.S. et al., 2007. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system (by Nature Transmissible ulcerative colitis caused by T-bet deficiency in the immune system). Cell. 131:33), showing the role of bacteria in this disease process. In humans, shifts in GI bacterial populations have also been associated with IBD (Lepage, P. et al., 2005. Biodiversity of the mucosa-associated microbiota is stable along the distal digestive tract in healthy individuals and patients with IBD (mucosa-associated small organism Population biodiversity is stable along the distal alimentary tract in healthy individuals and IBD patients). Inflamm. Bowel Dis. 11:473; Scanlan et al., 2006. Culture-independent analyzes of temporal variation of the dominant fecal microbiota and targeted bacterial subgroups in Crohn's disease (culture-independent analysis of temporal variation in faecal-dominant microbiota and directed bacterial subgroups in Crohn's disease). J. Clin. Microbiol. 40:3980; Frank, D.N. et al., 2007. Molecular-phylogenetic Characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl. Acad. Sci. USA. 104:13780).

Studies of such diseases as asthma have shown that those who suffer from the condition have fewer GI Bacteroides populations than the normal non-asthmatic population (Bjorksten, B. 1999. The environmental influence on childhood asthma) .Allergy.54:517). Additional evidence from epidemiological studies has shown a link between altered GI microbiota and atopic eczema and rheumatoid arthritis (Penders, J. et al., 2007. Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study (Intestinal Microbiota Composition and Formation of Heterotopic Phenomena in Infants: A KOALA Birth Cohort Study). Gut.56:661; Kalliomaki, M. and E. Isolauri.2002. Pandemic of atopic diseases-alack of microbial exposure in early infancy?. Curr. Drug Targets Infect. Disord. 2:193; Kalliomaki, M. and E. Isolauri, 2003.Role of the intestinal flora in the development of allergy (the role of the intestinal flora in the development of allergy).Curr.Opin.Allergy Clin.Immunol.3:15). In addition, several epidemiological and clinical reports have been published Increased incidence of immune-related disorders such as IBD, asthma, diabetes, rheumatoid arthritis, multiple sclerosis, and cancer (Luptin, J.R., 2004. Microbial degradation products influence colon cancer risk: the butyrate controversy Colon cancer risk: the butyrate paradox). J. Nutr. 134:479; Bjorksten, B. 1999. The environmental influence on childhood asthma. Allergy. 54: 517; Frank, D.N. et al People, 2007. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc.Natl.Acad.Sci.USA.104:13 780), whose rapidity cannot be solely attributed to an increase in genetic prognosis (Noverr, M.C. and G.B. Huffnagie. 2004. Does the microbiota regulate immune responses outside the gut? (Does the microbiota regulate immune responses outside the gut?). Trends Microbial. 12:562).

Contents of the invention

The present invention relates to cellular components, compositions containing such components or derivatives thereof, and methods for modulating inflammatory responses.

More specifically, in one embodiment, the present invention relates to a cellular component or derivative thereof lysed from, produced from and/or isolated from one or more bacterial species derived from the genus Bacteroides. In another embodiment, the present invention relates to compositions comprising such cellular components or derivatives thereof.

In another embodiment, the present invention relates to a genetically modified form of a bacterium from the genus Bacteroides. In another embodiment, the present invention relates to a composition comprising a genetically modified form of a bacterium from the genus Bacteroides.

In another embodiment, the invention relates to a method for treating, delaying the onset (including reducing the risk of developing) or reducing the symptoms of inflammation of the body or gastrointestinal tract in an individual, and more particularly, to treating one or more A method of delaying the onset or reducing the symptoms of an inflammatory disorder/disease comprising inflammation of the body or gastrointestinal tract, e.g., irritable bowel syndrome, Crohn's disease or colitis and/or related diseases Such as diabetes, asthma, multiple sclerosis, cancer, rheumatoid arthritis, gingivitis, atopic diseases, eg, hay fever, food allergies, eczema, rhinitis, dermatitis, conjunctivitis, atopic syndrome, and pore horns Alzheimer's disease, eye inflammatory disease, stroke, cardiovascular disease, depression, atherosclerosis, and hypertension. These methods include administering a gene comprising one or more species from the genus Bacteroides, a genetically modified form of a bacterium from the genus Bacteroides, or a drug lysed from, produced from, and/or isolated from a bacterium from the genus Bacteroides. Cellular components or derivatives thereof.

Additional embodiments of the invention will be apparent from the following detailed description.

Detailed ways

There are two main classes of bacteria found inside the human gastrointestinal tract: Gram-positive and Gram-negative bacteria, which are defined primarily by differences within the bacterial cell wall components. Lipopolysaccharide (LPS) is an integral component of the cell wall of Gram-negative bacteria, whereas teichoic acid (TA), lipoteichoic acid (LA) and peptidoglycan (PD) are associated with the cell wall of Gram-positive bacteria.

These diverse components are recognized by human epithelial cells to which bacterial cells can bind via adhesion proteins or ligands and elicit a cellular response. In addition to intact bacterial cells, various cell wall components (LPS, TA, LA, and PD) that form pathogen-associated molecular patterns (PAMPs) (also known as microbe-associated molecular patterns (MAMPs)) can also interact with host cells . These components are released during growth or when bacteria are engulfed by host defense cells or lysed by antibiotics. Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) linked to innate immune responses via NF-κB. Whole intact bacterial cells or MAMP alone can bind to PRRs (such as TLRs) on host epithelial cells to elicit specific cellular responses (Muta, T and K. Takeshige, 2001. Essential roles of CD 14 and lipopolysaccharide-binding protein for Activation by distinguished ligands in LP S preparations (Key role of CD 14 and lipopolysaccharide-binding protein on activation by distinguished ligands in LPS preparations). Eur.J.Biochem.268(16):4580). Whole bacteria can also be phagocytosed by GI dendritic cells, which then migrate to the mesenteric lymph nodes, where they induce unstimulated B cells to produce IgA (Macpherson, A.J. and T. Urh, 2004. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria (induction of protective IgA by intestinal dendritic cells carrying commensal bacteria). Science:303:1662). It has been suggested that the secretion of IgA by GI cells may be the means by which GI microorganisms affect the host immune system (Cerutti, A, 2008. The regulation of IgA production class switching (regulation of IgA production class switching). Nature Rev. Immunol.8:421; Tezuka et al., 2007. Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells (regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells). Nature 448:929). Alternatively, MAMP molecules that function in antigen (Ag) capacity can be transported across gastrointestinal (GI) epithelial cells where they are picked up by binding proteins and carried in serum. They are then delivered to immune cells, for example, with TLRs that have been identified as PAMP-specific PRRs (Doyle, S.L. and L.A. O'Neill, 2006. Toll-like receptors: from the discovery of NF-κB to new insights into transcriptional regulations in innate immunity (Toll-like receptors: from the discovery of NF-κB to a new understanding of transcriptional regulation in innate immunity). Biochem.Pharmacol.72(9):1102), in the immune cells, these MAMP molecules bind And initiate the phosphorylation of inhibitory κB kinase 2 (IKK). Once bound, activates nuclear factor-kβ (NF-κB).

Nuclear factor-kβ is a family of fast-acting transcription factors, ie transcription factors that exist in the cell in an inactive state and do not require new proteins for activation. Thus, activation of TLR receptors results in fairly rapid changes in genetic expression. In the inactive form, NF-κB is present in the cytoplasm and binds to the inhibitory protein IkBa. Once TLR receptors are activated by PAMPs, the enzyme IkB kinase (IKK) is activated, phosphorylating inhibitory proteins and releasing NF-κB in an activated state. This NF-κB then translocates to the nucleus, where it binds to response elements (REs), recruits other proteins and ultimately activates RNA polymerase. This leads to transcription of DNA into mRNA, which is translated into protein in the cytoplasm and subsequently alters cellular function (Brasier, A.R. 2006, The NF-κB regulatory network. Cardiovasc. Toxicol. 6(2): 111; Gilmore, T.D, 1999. The Rel/NF-κB signal transduction pathway: introduction (Rel/NF-κB signal transduction pathway: Introduction). Oncogene 18(49):6842). In general, activation of specific genes by NF-κB produces specific cellular/physiological responses, such as inflammatory or immune responses (Nelson, D.E. et al., 2004. Oscillations in NF-κB signaling control the dynamics of gene expression (NF-κB signaling Oscillations in conduction control the dynamics of gene expression). Science: 306(5696): 704). Altering the bacterial population of the gut or delivering different molecular components (MAMPs) to GI epithelial cells can positively alter genetic expression and subsequent deleterious immunological responses, thus modulating or preventing inflammatory states and their associated diseases. For example, preventing the onset of inflammation by blocking and/or altering TLR receptor responses (including subsequent cytokine release) and thus preventing the NF-κB inflammatory cascade is beneficial in preventing cell proliferation and supporting apoptosis (Lin, W-W and M. Karin, 2007. A cytokine-mediated link between innate immunity, inflammation, and cancer (cytokine-mediated link between innate immunity, inflammation, and cancer). J. Clin. Invest. 117 (5): 1175-1183) and elimination and/or minimize the inflammatory disease process in the host.

Generally, the immune system consists of two distinct components: innate immunity and adaptive immunity. These two systems cooperate to protect the host from invasive pathogens. The innate immune system is broad and recognizes molecular patterns such as MAMPs, and includes general molecular components and cellular mechanisms such as TLRs, monocytes and neutrophils. Since it is designed to prevent infection, it includes skin/epithelial cells and mucosal secretions, which provide the first barrier in preventing the adhesion and invasion of pathogenic organisms. Due to the rapid onset of action, the natural immune system is rapidly activated and can neutralize threats against the host within hours of exposure, preventing an inflammatory response. Once this system fails, the adaptive immune response eliminates the invading organism.

The anatomy of the human host defense system is designed to protect against pathogenic microbial invaders. These mechanisms include physical barriers (epithelium in the layers of the skin, respiratory, genitourinary and gastrointestinal tracts) and cell surface receptors (CSRs) that recognize pathogens and "self" and upon recognition trigger specific cellular/genetic responses. In general, both the challenge of infection and the establishment of normal gastrointestinal flora require bacterial cell adhesion to host cell surfaces. Adhesins are molecules that mediate adhesion and are generally present on the surface of bacterial cells or on the tips of bacterial cilia or pili (Hultgren, S.J et al., 1993. Pilus and nonpilus bacterial adhesives: assembly and function in cell adhesion (pilus and nonpilus bacterial adhesives: assembly and function in cell adhesion) Non-pilus bacterial adhesion proteins: assembly and function in cell adhesion). Cell. 73:887).

The entire bacterial cell may not be required to initiate or prevent activation of the host immune defense system. Molecules derived from specific bacteria have been shown to promote immune function within the host. The monomolecular polysaccharide A (PSA) derived from Bacteroides fragilis exhibits the ability to direct the development of the immune system in germ-free mice (Mazmanian, S.K. et al., 2005. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system (immunomodulatory molecules of symbiotic bacteria direct the maturation of the host immune system). Cell.122:107). Colonization of germ-free mice with B. fragilis or treatment with purified PSA protects against induction of experimental IBD and reduces proinflammatory cytokines (such as TNF, IL-17, and IL-23) associated with disease in these models Secretion (Mazmanian, S.K. et al., 2008. A microbial symbiosis factor prevents intestinal inflammatory disease (microbial symbiosis factor prevents intestinal inflammatory disease). Nature. 453:620). In addition, colonization of germ-free mice with Bacteroides polymorpha showed that this bacterium does not produce an inflammatory response (Hooper, L.V. et al., 2001. Molecular analysis of commensal host-microbial relationships in the intestine (Molecular analysis of commensal host-microbial relationships in the intestine Analysis). Science 291:881), which in turn may reduce or prevent disease processes associated with and exacerbated by chronic inflammation.

Matrix metalloproteinases (MMPs) are a family of enzymes involved in several different physiological processes, including embryonic development, tissue remodeling, apoptosis, arthritis, and host immunity. The target gene enzyme (Matrylisin) (MMP-7) is known to play a role in both tissue repair and mucosal defense (Bals, R. et al., 1998. Mouse beta-defensin 1 is a salt-sensitive antimicrobial peptide present in epithelia of the lung and urigenital tract (mouse β-defensin 1 is a salt-sensitive antimicrobial peptide present in the epithelium of the lung and urogenital tract). Infect.Immun.66:1225). Several studies have shown that this enzyme also plays a role in the degradation and processing of several other matrix proteins, including elastin, proteoglycans, core proteins, and serpins (Murphy, G. et al., 1991. Matrixmetaloproteinase degradation of elastin, type IV collagen and proteoglycan. Aquantitative comparison of the activities of 95 kDa and 78 kDa gelatinases., stromylesins-1 and-2 and punctuated metalloproteinases (PUMP) (matrix metals of elastin, type IV collagen and proteoglycans Protease degradation: a quantitative comparison of the activities of 95 kDa and 78 kDa gelatinases, stromelysin-1 and -2, and truncated metalloproteases (PUMPs). Biochem. J. 277:277; Sires, I., G. et al. 1993.Degradation of entactin by matrixmetaloproteinases.Susceptibility to matrylisin and identification of cleavage sites (degradation of nestin by matrix metalloproteinase: identification of susceptibility to matrylisin and cleavage sites). J.Biol.Chem.268:2069; Halpert, L. et al.,1996.Matrilysin is expressed bylipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteolytic substrate for the enzyme (Matrilysin is expressed by lipid-laden macrophages in atherosclerotic lesions expressed at potential rupture sites in lesions and localized to areas of deposition of pluripotent glycan, the proteolytic substrate of the enzyme). Proc. Natl. Acad. Sci. USA. 93:9748).

Unlike many enzymes within the MMP family, the target gene enzyme (matrylisin) is expressed by uninjured exocrine and mucosal cells, especially those with high bacterial loads (Wilson, C.L. et al., 1999. Regulation of intestinal alpha-defensin activation by the metalloproteinasematrilysin in innate host defense (regulation of intestinal α-defensin activation by metalloproteinases in natural host defense). Science 286:113; Saarialho-Kere, U.K. et al., 1993. Divergent mechanisms regulate interstitial collagenase and 92 kDa gelatinase expression inhuman monocyte-like cells exposed to bacterial endotoxin (divergence mechanism regulates expression of interstitial collagenase and 92 kDa collagenase in human monocyte-like cells exposed to bacterial endotoxin). J.Biol, Chem.268:17354) . Although the target gene enzyme (matrylisin) is not bactericidal, it appears to be required for the activation of cryptin (intestinal α-defensin) with broad antimicrobial activity (Ouettlette, A.J. et al., 1994. Mouse Paneth cell defensin: primary structures and antibacterial activities of numerous cryptdin isoforms. Infect. Immun.62:5040; Ouellette, A.J. and S.E.Selsted.1996.Paneth cell defensesins:endogenouspeptide components of intestinal cell defense (Paneth cell defensins: endogenous peptide components of intestinal cell defense).FASEB (Fed.Am.Soc.Exp.Biol.J .) 10:1280, and thus plays a central role in natural host defense at mucosal surfaces. Colonization of germ-free mice with Bacteroides polymorpha cultures causes the target gene enzyme (matrylisin) to be expressed by Pane, suggesting that the GI cell wall Host immune defenses against pathogens are enhanced by exposure to this bacterium. Evidence also suggests that intact bacteria are not required to elicit a positive host immune response. When human colonic cell cultures (HT29) were exposed to bacterial culture filtrate When the target gene enzyme (matrylisin) expression occurs, even when the culture medium is treated with cycloheximide and/or antibiotics (Lopez-Baodo, Y.S. et al., 2000. Bacterial exposure induces and activates matrilysin in mucosal epithelial cells (bacterial exposure Induction and activation of matrilysin in mucosal epithelial cells). J. Cell Biol. 148:1305). Earlier evidence also showed that soluble bacterial factors or modulin stimulate immune responses/cytokine responses (Henderson, B. et al. People, 1998. Bacterial modulins: a novel class of virulence factors which cause host tissue pathology by inducing cytokine synthesis (bacterial modulins: a new class of virulence factors that cause host tissue pathology by inducing cytokine synthesis). Microbiol. Rev. 60:316; Wilson, M.R. Seymour and B. Henderson. 1998. Bacterial perturbation of cytokine networks. Infect. Immun. 66: 2401). These data suggest the presence of bacterial soluble factors. Such molecules from Bacteroides species could be used in the future to modulate host inflammatory/disease responses. Cellular components isolated from or synthesized from any species derived from within the genus Bacteroides can be isolated and used to modulate inflammatory responses, thus reducing the occurrence or preventing the onset of inflammation and associated diseases.

The use of gnotobiotic animals in studies designed to elucidate the influence of microbes on the development of the host immune system has yielded several insights. For example, germ-free mice showed impaired development and maturation of isolated lymphoid follicular fluid, which was corrected when gut bacteria normally present in the host's GIT were introduced (Hultgren, SJ et al., 1993. Pilus and nonpilus bacterial adhesins: assembly and function in cell adhesion (pilus and nonpilus bacterial adhesins: assembly and function in cell adhesion). Cell 73:887). Furthermore, germ-free mice have shown a decrease in secretory immunoglobulin A (IgA) in the gut (Peterson, DA et al., 2007. IgAresponse to symbiotic bacteria as a mediator of gut homeostasis (targeting commensal bacteria as mediator of gut homeostasis Cell Host Microbe 2:328), the functions of the secretory immunoglobulin include coating pathogenic bacteria to prevent adhesion to host GI epithelial cells and/or binding antigenic bacteria together to facilitate elimination, thereby Prevents the invasion of pathogenic organisms and the resulting infection, thus excluding the onset of inflammatory reactions. Although the exact role is still unclear, evidence is emerging to support the notion that commensal bacteria are actively involved in the protective secretion of IgA. IgA production is induced by unstimulated B cells when dendritic cells carrying commensal bacteria or MAMPs migrate to mesenteric lymph nodes where unstimulated B cells are present (Suzuki, K. et al., 2004. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut (Abnormal expansion of segmented filamentous bacteria in the IgA-deficient gut). Proc. Natl. Acad. Sci. 101:1981), showing one way in which the gut microbiota affects the host immune system. Recent findings also provide additional evidence that commensal bacteria affect the function and IgA secretion of specialized mucosal dendritic cells, thereby affecting the subsequent host intestinal immune response (Tezuka, H. et al., 2007, Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells (regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells). Nature 448:929). Previous evidence has also shown that it is the bacterial population in the host GIT that directs the glycosylation of luminal cell surface receptors of intestinal epithelial cells, which also affects pathogenic adhesion (Bry, L. et al., 1996. A model of host -microbial interactions in an openmammalian ecosystem (host-microbe interaction model in an open mammalian ecosystem). Science 273:1380). Additionally, several other microbial fermentation products have been shown to have various effects, including adenosine triphosphate (ATP) production (Atarashi, K. et al., 2008. ATP drives lamina propria T ₈ l7 cell differentiation (ATP drives lamina propria T ₈ 17 cells differentiation). Nature 455:808). Several other microbial fermentation products have also been shown to have immunomodulatory effects. Treatment of mice with antibiotics followed by exposure to the parasite Encephalitizoan cuniculi and subsequent treatment with DNA isolated from normal gut bacteria resulted in a reduced parasite burden (Hall, J. et al., 2008. Commensal DNA limits regulatory T cell conversion and is natural adjuvant of intestinal immune responses (commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune response). 2008.Immunity.29:637). These studies demonstrate that the cellular components/compositions of the invention alone can positively affect the host immune response, providing further evidence that the cellular components can benefit the host. More specifically, reconstitution of germ-free mice with bacterial populations free of Bacteroidete species failed to restore the correct immune balance in the host (Ivonav, II. et al., 2008. Specific microbiota direct differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine (Specific groups of small organisms direct the differentiation of IL-17-producing helper T cells in the small intestinal mucosa. Cell Host Microbe 4:337), which provides additional evidence for Bacteroides Species within and/or cellular components isolated from these bacteria/compositions of the invention can be beneficially used to support host health and modulate inflammatory responses and related diseases.

The gastrointestinal microbiota plays an important role in maintaining host and GI health and preventing disease. In addition to the engagement of bacteria with host cell surface receptors, it appears that it is the molecular dialogue between molecules produced by bacterial cells and/or components of bacterial cells, together with host immune receptors, that enables small biota to confer host resistance. Sickness. Thus, a composition comprising one or more species of Bacteroides or modified forms, cellular components or groups thereof from the genus Bacteroides may be used to modulate any of the relevant disease states for the benefit of the host. Derivatives of components (including fragments thereof, molecular complexes/networks derived therefrom, molecules derived therefrom) and/or synthetic or semi-synthetic analogues thereof and/or mixtures of any of these substances.

Accordingly, in various embodiments, the present invention relates to cellular components, modified bacteria, compositions and methods for modulating inflammatory responses and/or related disease states. More specifically, in one embodiment, the present invention relates to a cellular component or derivative thereof lysed from, produced from and/or isolated from one or more bacterial species derived from the genus Bacteroides, e.g. , synthetically derived molecules based on molecules/molecular patterns in species derived from within the genus Bacteroides. In another embodiment, the present invention relates to a genetically modified form of a bacterium from the genus Bacteroides. In another embodiment, the present invention relates to compositions comprising cellular components or derivatives thereof from one or more bacteria of the genus Bacteroides or Genetically or chemically modified forms.

Probiotic compositions comprising bacteria from the genus Bacteroides are described in US Patent Application Serial No. 12/255,152, US 2009/0110664, filed October 21, 2008, which is incorporated herein by reference in its entirety.

Although the mechanisms are not thoroughly elucidated, evidence is available for associations between small biota and various disease states. Thus, one or more species from the genus Bacteroides or genetically or chemically modified forms thereof, or cellular components thereof or derivatives of such cellular components (including molecular complexes/networks therefrom, molecules therefrom ) and/or synthetic or semi-synthetic analogs thereof (including mixtures thereof) may be used to modulate inflammation, i.e. inflammation of the body or gastrointestinal tract in an individual, and more specifically, to treat one or Delaying the onset or reducing the symptoms of various inflammatory conditions/diseases including inflammation of the body or gastrointestinal tract and/or related diseases such as diabetes mellitus, irritable bowel syndrome, Crohn's disease, Colitis, asthma, multiple sclerosis, cancer, including cancers such as colon cancer, colorectal cancer, prostate cancer, bladder cancer, lymphoma cancer, hepatocellular carcinoma, from bone, cartilage, muscle, fat or vascular tissue, bronchi, esophagus , peritoneal tumors of the thyroid, ovary, breast, pancreas, liver and stomach, lung tumors, brain tumors, sarcomas, rheumatoid arthritis, gingivitis, atopic diseases including but not limited to hay fever, food allergies, eczema, Rhinitis, dermatitis, conjunctivitis, atopic syndrome and keratosis pore, ocular inflammatory disease, stroke, hypertension, cardiovascular disease, depression and atherosclerosis and/or any associated disease state. In the context of the present disclosure, delaying the onset of a disease or condition includes reducing the risk of developing the disease or condition. These methods include administering a composition of the invention to an individual suffering from or at risk of such a disease.

Cellular components isolated from or synthesized from Bacteroides can be isolated and used to modulate inflammatory responses, thus reducing the occurrence or preventing the onset of the aforementioned diseases and/or conditions. Cellular components and derivatives thereof include any molecule or molecules from bacterial species of the genus Bacteroides, symbiotic factors, cell wall components, molecules produced by bacterial cells, cellular components/cell fragments therefrom, Molecular complexes/networks, molecules derived therefrom and/or synthetic or semi-synthetic analogues of these substances, including those prepared according to extreme biological synthesis techniques, and/or mixtures of any of these substances, which Can be used to modulate inflammation and/or any related disease state as described herein.

In one embodiment, the present invention relates to a cellular component or derivative thereof lysed from, produced from and/or isolated from any species derived from the genus Bacteroides. In another embodiment, the present invention relates to genetically modified or extremologically synthesized forms of such bacteria or cellular components thereof.

Bacteria used in the preparation of the disclosed cell component preparations include, but are not limited to, any species within the genus Bacteroides, such as Bacteroides polymorpha (ATTC29148), Bacteroides fragilis (NCTC9343), Bacteroides vulgaris (ATCC8482), Bacteroides Bacteroides (ATCC8503), B. ovatus, B. stercoris, B. merdae, B. uniformis, B. escherichia ( B.eggerithii) and Bacteroides faecalis (B.caccae), with B. fragilis as the model strain. In a particular embodiment, the bacterium is selected from the group consisting of Bacteroides polymorpha, Bacteroides fragilis, Bacteroides vulgaris, Bacteroides gibberii, Bacteroides ovale, Bacteroides faecium, Bacteroides monomorpha, Bacteroides escheri and Bacteroides faecalis.

In a specific embodiment, one or more cellular components of the invention may be directed against appropriate intestinal epithelial cell surface receptors to reduce the binding of pathogens or cellular components of pathogens.

In another embodiment, the cellular component comprises, for example, a cell wall component selected from the group consisting of lipopolysaccharides, proteins, sugars, lipids, lipoproteins, glycoproteins, and combinations thereof. In another embodiment, cellular material includes DNA or RNA, such as 16S RNA, messenger RNA, ribosomal RNA, and the like.

In another embodiment, the cellular component comprises a molecule or molecules produced by a species within the genus Bacteroides.

In another embodiment, the cellular component is produced by mimicking the de novo biosynthesis of any cellular component from any bacterial species from the genus Bacteroides.

The cellular component composition may be provided as a single molecule or a combination of molecules, or any combination thereof, lysed from a bacterial cell or derived synthetically from a molecule obtained from a bacterial species of the genus Bacteroides. Those skilled in the art will appreciate that Bacteroides molecules can be lysed directly from the bacteria or manufactured synthetically based on any molecular component of any Bacteroides species.

Examples of cellular components include, but are not limited to, cell fragments, molecular complexes or networks, cell wall components and/or unique products/molecules produced (including any de novo synthesis) by any species within the genus Bacteroides or by any genetically modified species (all The above-mentioned genetically modified species may include, but not limited to, site mutations, insertions, deletions or modifications of genetic material from any source (viruses, bacteria, humans, etc.), any Bacteroides cells and/or genetically modified bacterial cells Any molecule and/or any product/synthetic or semi-synthetic analog of the molecule and any synthetic or semi-synthetic analog of any of these molecules from any species of this genus produced, as skilled in the art Personnel will understand. Examples of methods by which such cellular components and modified bacteria may be obtained are provided. Additional methods will be apparent to those of skill in the art upon review of the present disclosure.

混合器中，以便机械地破坏膜。可选地，可以细胞置于引起膜涨破的低渗溶液中。也可以迫使细胞悬液穿过小空间（液体均化）,导致细胞膜破坏。一旦裂解，分离一般地始于梯度离心方法，随后是取决于细胞组分的分离技术，随后是额外分离和纯化方法。这些方法可以包括但不限于例如，使用多种溶液（例如，磷酸盐缓冲溶液、盐溶液或硫酸铵）用梯度离心提取和/或用于分离蛋白质的Soxhlet法、用于分离核酸的乙醇法和用于分离脂溶性组分的苯酚法。用于进一步纯化的额外方法包括但不限于透析和/或过滤/凝胶过滤和/或多种形式的使用适宜柱的高效/高压液相色谱（HPLC）。其他方法可以包括但不限于，用于进一步分离、纯化和鉴定/扩增和/或用于生物学活性测定法的多种形式的电泳法，如十二烷基硫酸钠聚丙烯酰胺凝胶电泳（SDS-PAGE）、分光光度法、酶联免疫吸附测定（ELISA）、荧光印迹法和聚合酶链反应。还可以使用的其他方法包括利用克隆性DNA载体和扩增的核酸扩增法（常称作重组DNA技术或基因工程）。本领域技术人员将理解，可以出于制造和生物学测定目的，将多种技术用于裂解和后续的分离、鉴定和扩增和产生本发明的组合物/细胞组分。In one embodiment, methods for producing cellular components of the invention begin with lysis of bacterial cells, which results in disruption of the cell membrane and subsequent release of cellular contents (molecules, organelles, etc.). Methods of lysing cells include, but are not limited to, mechanical methods (e.g., mixing), optical methods (e.g., laser), chemical methods (e.g., using surfactants such as sodium lauryl sulfate), acoustic methods (e.g., sonication) , electrical methods (eg, voltage), osmotic methods (eg, hypotonic solutions), or enzymatic methods (eg, lysozyme). A common method involves placing the cells in a

in a mixer to mechanically disrupt the membrane. Alternatively, the cells can be placed in a hypotonic solution that causes the membrane to burst. Cell suspensions can also be forced through small spaces (homogenization of liquids), resulting in disruption of cell membranes. Once lysed, isolation generally begins with gradient centrifugation methods, followed by separation techniques depending on the cellular components, followed by additional isolation and purification methods. These methods can include, but are not limited to, for example, extraction with gradient centrifugation using various solutions (e.g., phosphate buffered saline, saline, or ammonium sulfate) and/or the Soxhlet method for the separation of proteins, the ethanol method for the separation of nucleic acids, and Phenol method for separation of fat-soluble fractions. Additional methods for further purification include, but are not limited to, dialysis and/or filtration/gel filtration and/or various forms of high performance/high pressure liquid chromatography (HPLC) using suitable columns. Other methods may include, but are not limited to, various forms of electrophoresis, such as sodium dodecyl sulfate polyacrylamide gel electrophoresis, for further isolation, purification and identification/amplification and/or for assays of biological activity (SDS-PAGE), spectrophotometry, enzyme-linked immunosorbent assay (ELISA), fluorescent blotting and polymerase chain reaction. Other methods that may be used include nucleic acid amplification using clonal DNA vectors and amplification (often called recombinant DNA technology or genetic engineering). Those skilled in the art will appreciate that a variety of techniques may be used for lysis and subsequent isolation, identification and amplification and production of compositions/cellular components of the invention for manufacturing and biological assay purposes.

Cellular components (including their various conjugates) including but not limited to e.g. proteins (endotoxins, transmembrane proteins, integral proteins and enzymes), glycoproteins, components of the periplasm, glycolipids, lipopolysaccharide (LPS) , MAMP/PAMP, cell surface molecules (antigens, adhesion proteins, etc.), cytoplasmic molecules or products, lipoproteins, porins, peptidoglycans, sugars, peptides, lipid A, O polysaccharides, phospholipids, lipids qualitative or genetic components such as DNA, RNA and nucleic acids. In a specific embodiment, the cellular components include LPS (lipopolysaccharide), DNA/RNA/nucleic acid, O-polysaccharide, lipid A, endotoxin and/or MAMP. In another embodiment, the cellular components include O polysaccharides and/or lipid A.

In addition, cellular components include, but are not limited to, those produced and secreted by any bacterium from the genus Bacteroides via any system, including but not limited to ABC-transporters (ATP-binding cassette transporters, including but not limited to types I-VI). Release of unique molecules such as proteins, sugars, lipids and combinations or derivatives thereof, plasmids, nucleic acids, antibiotics and bacteriocins, metabolites and outer membrane molecules including but not limited to eg periplasmic or cytoplasmic material.

Cellular components include, but are not limited to, synthetic or semi-synthetic analogs of any of the previously described cellular components, including but not limited to pharmacophore (often used to refer to the active site of a compound that is body interactions, molecular structures that produce the desired result) or auxophores (molecular components that are not part of the active site but that if modified lead to modulation of biological activity).

Derivatives of said cellular components are also included in the present invention. These derivatives may include modified forms including, but not limited to, addition, removal or alteration of atoms within a molecule and/or addition, removal or alteration of one or more molecules or addition or excised molecules within a molecular network/complex Atom/molecule or group. For example, include addition of ethyl or hydroxyl groups, substitution of hydroxyl groups with amines, modification of functional groups such as by substitution of methyl groups for mercapto groups, substitution of sulfur for example oxygen atoms or any molecular displacement or alteration of stereogenic centers to form new stereoisomers, change of principal Chain configuration to form new isomers or any other alteration in which specific structural or chemical changes result in modulation of activity or potency. Additions to cellular component structures include, for example, the extension of saturated carbon chains by 1 to 5 atoms (methyl to pentyl) or more, or the addition of methylamino groups, chain branching, ring modifications, or the addition of groups such as amino or sulfo base) position from ortho to ortho, which can lead to improved biological activity/host response. Synthetic analogs include homologation of molecular structures (e.g. any molecular group differing by 1 constant unit such as CH2-) and conversion of backbone or substituents from linear to cyclic or vice versa (e.g. modification to ring amino acid or nucleic acid ring structure). Synthetic derivatives of cellular components include modifying groups with isosteric groups to form bioisosteres with chemical or physical similarity and similar biological activity (a chemical functional group is replaced by another chemical group that results in similar biological activity ). For example, this includes, but is not limited to, molecules that have a number of valence electrons or those molecules that do not have the same number of atoms but have similar outer electrons. These isosteric groups include, but are not limited to, monovalent atoms such as chlorine, fluorine or hydroxyl, divalent atoms such as oxygen and selenium, and ring equivalents such as benzene or thiophene. Nonclassical bioisosteres that do not have a similar number of atoms or valence electrons, but have similar biological activity include, but are not limited to, modified forms of carbonyl or carboxyl groups or heterocyclic aryl groups such as oxazole, thiophene, imidazole, and the like. Those skilled in the art will understand that this short list is illustrative of only a few of the many specific embodiments that are encompassed within the invention.

A suitable amount of Bacteroides bacteria can be produced using a fermentation process. For example, sterile, anaerobic fermenters can be filled with media such as glucose, polysaccharides, oligosaccharides, mono- and disaccharides, yeast extract, protein/nitrogen sources, macronutrients and micronutrients (vitamins and minerals) , and a culture of the desired Bacteroides bacterium can be added to the medium. During fermentation, concentration (colony forming units/gram), purity, safety and absence of impurities can be monitored to ensure a quality final result. After fermentation, the Bacteroides bacterial cells can be isolated from the culture medium using a variety of well-known techniques such as filtration, centrifugation, etc., and the cell components are lysed and/or separated from other cellular components. The isolated cellular components can be dried, for example, by lyophilization, spray drying, heat drying or a combination thereof, adding a protective solution/medium if necessary.

In another embodiment, the cellular component is produced by mimicking the de novo biosynthesis of any cellular component from any bacterial species from the genus Bacteroides.

A genetically modified bacterium from the genus Bacteroides suitable for use in the present invention consists of any genetic alteration, including but not limited to specific changes in genes (position site-directed mutagenesis), genetic modification by insertion or deletion of specific genes (using restriction enzymes) and/or plasmids (e.g., R-factor plasmids) or viruses (e.g., shuttle viruses), addition from any source (viruses, animals, Covalent modification of any genetic material and nucleotides/genes/genomes of plants, yeast, etc.).

The present invention also relates to compositions comprising the disclosed cellular components or derivatives thereof, bacteria of the genus Bacteroides or genetically modified forms thereof, such compositions are referred to herein as compositions of the invention, and also to the use of Methods of such compositions as described herein.

Compositions of cellular components or derivatives thereof, bacteria or genetically modified forms thereof as described can be started from a suitable medium to which suitable protective agents can be added for molecular protection. Examples of suitable protectants include, but are not limited to, distilled water, polyethylene glycol, sucrose, trehalose, skim milk, xylose, hemicellulose, pectin, amylose, pullulan, xylan, arabinogalact Polysaccharides, starches (for example, potato starch or rice starch), and polyvinylpyrrolidone.

In another embodiment, the disclosed cell component compositions can include an amount of a bacterial cell component and optionally one or more physiologically acceptable carriers. In a specific embodiment, the carrier is a pharmaceutically acceptable carrier, and the composition is adapted for administration to a human or other animal. A carrier can be provided to facilitate delivery to a subject animal in need thereof. As used herein, the term "carrier" is intended to refer broadly to any substance (e.g., tablet or liquid) or article (e.g., capsule shell or polymer matrix). Those skilled in the art will understand that the carrier should not significantly inhibit the intended value of the cellular component to the subject. As described in further detail below, administration may be by any desired route, including oral, injection, inhalation, topical or other known routes of administration.

The composition of the present invention comprising bacteria of the genus Bacteroides and/or bacterial cell components of the genus Bacteroides can be prepared in various administration forms, such as capsules, suppositories, tablets, food/drinks, inhalants, sublingual fluids, lotion, eye drops or ear drops etc. In another aspect, the composition of the invention may be provided as a semi-solid or filter cake or in powder form. In one embodiment, optionally, the composition of the present invention may comprise various pharmaceutically acceptable excipients, such as microcrystalline cellulose, mannitol, dextrose, skim milk powder, polyvinylpyrrolidone, starch or combinations thereof and /or any of the excipients mentioned herein.

The present disclosure provides compositions of cellular components from any suitable bacterial species of the genus Bacteroides, and the use of the disclosed compositions of cellular components to treat animals such as humans, horses, rats, mice, ruminants, primates , delaying the onset of one or more gastrointestinal or systemic inflammatory conditions or one or more inflammatory conditions/diseases in , monkeys, hamsters, rabbits, dogs, cats and various bird and fish species, Including systems and methods for reducing the risk of developing and/or reducing symptoms thereof, said inflammatory conditions/diseases include inflammation of the body or gastrointestinal tract and/or related diseases, such as diabetes mellitus, irritable bowel syndrome, Crohn's disease, Colitis, asthma, multiple sclerosis, cancer, including cancers such as colon cancer, colorectal cancer, prostate cancer, bladder cancer, lymphoma cancer, hepatocellular carcinoma, from bone, cartilage, muscle, fat or vascular tissue, bronchi, esophagus , peritoneal tumors of the thyroid, ovary, breast, pancreas, liver and stomach, lung tumors, brain tumors, sarcomas, rheumatoid arthritis, gingivitis, atopic diseases including but not limited to hay fever, food allergies, eczema, Rhinitis, dermatitis, conjunctivitis, atopic syndrome and keratosis pore, ocular inflammatory disease, stroke, hypertension, cardiovascular disease, depression, atherosclerosis, or rheumatoid arthritis and/or any associated disease state. A disclosed cellular composition as described herein, a "composition of the invention" can be delivered to a host to attenuate, delay or reduce symptoms of gastrointestinal or systemic inflammation of the previously mentioned conditions. In a specific embodiment, these methods are practiced in humans.

In one embodiment, the cellular components and/or compositions of the invention are provided in lyophilized form according to conventional techniques. An example of a suitable lyophilization method may start with a medium carrying a suitable carrier including, but not limited to, one or more protectants, buffers, stabilizers, more specifically distilled water, polyethylene glycol, sucrose, seaweed Sugar, skimmed milk, xylose, hemicellulose, pectin, amylose, pullulan, xylan, arabinogalactan, starches (for example, potato starch or rice starch), polyvinylpyrrolidone, iron oxides , polydextrose, polyvinyl acetate phthalate, propylene glycol, shellac wax, sodium alginate, sodium bicarbonate, triethyl citrate, lactose, mannitol, sorbitan, sodium phosphate, sorbitol, parylene One or more of polysiloxane, sodium lauryl sulfate, croscarmellose sodium, lecithin, and xanthan gum.

In one embodiment, the compositions of the invention may be in sustained release (SR), extended release (ER, XR or XL), time release controlled release (CR) or continuous release (CR or Contin) form (for example, as a tablet , soft gels, suppositories or capsules) to release molecules over an extended period of time. These components may be embedded in a matrix of insoluble substances and/or conventional additives including, but not limited to, acrylics, chitin, polymers, materials that swell to form gels or matrices. Soluble fiber, insoluble fiber, microcrystalline cellulose, propyl gallate, coloring agent and/or hypromellose. In a specific embodiment, a sustained release, extended release, time release controlled release or continuous release form is used for oral administration.

In a specific embodiment, the cellular components or bacteria are delivered in a time-release, extended-release or sustained-release format. Examples of suitable formulation components include, but are not limited to, hypromellose, microcrystalline cellulose, magnesium stearate, milk protein, titanium dioxide, sodium citrate, propyl gallate, riboflavin, inulin, iron oxide , silicon dioxide, silicon dioxide, magnesium silicate, maltodextrin, chlorophyll, potato starch, calcium phosphate, sodium starch glycolate, turmeric, carbonate, carnauba wax, triacetin, polysorbate 80, formazan One or more of acrylic acid copolymer, chitin, acrylic acid, acryloyl, acrylyl, acryl, povidone, and stearic acid.

In one aspect, the disclosed cell component compositions/compositions of the invention can be prepared as capsules/soft gels. A capsule (ie, carrier) can be a hollow, generally cylindrical capsule formed from a variety of substances, such as gelatin, cellulose, sugars, hypromellose, and the like. Capsules may receive therein Bacteroides bacteria or cell components/compositions of the invention. Optionally and in addition to suitable Bacteroides bacteria or cell components/compositions of the invention, the capsules may contain, but are not limited to, coloring agents, flavoring agents, rice starch or other starches, glycerol and/or titanium dioxide.

In a second aspect, compositions of the invention may be prepared as suppositories. Suppositories may contain, but are not limited to, suitable Bacteroides bacteria or cellular components and one or more carriers, such as polyethylene glycol, gum arabic, acetylated monoglycerides, carnauba wax, cellulose acetate phthalate, Esters, corn starch, dibutyl phthalate, docusate sodium, gelatin, glycerin, iron oxide, kaolin, lactose, magnesium stearate, methylparaben, pharmaceutical glaze, povidone, nipagin Propyl Parkinate, Sodium Benzoate, Sorbitan Monooleate, Sucrose, Talc, Titanium Dioxide, White Wax and Coloring Agent.

In a third aspect, the composition of the invention may be prepared as a tablet. Tablets may comprise a suitable Bacteroides bacterium or cell component/composition of the invention and one or more tableting agents (i.e., carriers), such as calcium hydrogen phosphate, stearic acid, croscarmellose, , silica, cellulose and cellulose coatings. Tablets may be formed using direct compression, although those skilled in the art will appreciate that a variety of techniques may be used to form tablets.

In a fourth aspect, the disclosed compositions of the present invention may be formed into a food or beverage or alternatively as an additive to a food or beverage, wherein an appropriate amount of Bacteroides bacteria or cell components are added to the food or beverage to Food or drink administration vehicle. In a particular embodiment, the composition of the invention is an addition to chewing gum, lozenges, hard or soft candies or the like.

In a fifth aspect, the compositions of the present invention may be provided in a sublingual fluid, which may contain, but is not limited to, selected from the group consisting of water, sorbitol, glycerol, citric acid, potassium sorbate, and flavoring agents one or more components.

In a sixth aspect, the composition of the present invention may be provided in an oral rinse, which may comprise, but is not limited to, selected from the group consisting of water, ethanol, sorbitol, poloxamer 407, benzoic acid, flavorings, saccharin One or more components of sodium, sodium citrate, citric acid, and food-safe dyes.

In a seventh aspect, the compositions of the invention may be provided in a pressurized metered dose inhaler. Such inhalants may contain pressurized carriers, which may include, but are not limited to, 1,1,1,2-tetrafluoroethane (HFA-134A) and the like.

In an eighth aspect, the composition of the present invention may be provided in an eye drop solution comprising, but not limited to, a compound selected from the group consisting of benzalkonium chloride, edetate disodium, potassium chloride, water, bicarbonate One of sodium, sodium citrate, sodium chloride, sodium (dihydrogen or monohydrogen) phosphate, polyvinyl alcohol, povidone, nonanoyl EDTA, polyquaternium-1, and myristamidopropyldimethylamine or multiple components.

In a ninth aspect, the composition of the present invention may be provided in ear drops which may contain, but are not limited to, one or more components selected from the group consisting of benzalkonium chloride, glycerol and water.

In a tenth aspect, the compositions of the present invention may be provided in a lotion which may contain, but is not limited to, selected from the group consisting of water, glycerol, petrolatum, cetearyl alcohol, dimethicone, Fragrance, Ceteareth-20, Sodium Hydroxide, Methylparaben, Propylene Glycol, Diazolidinyl Urea, Disodium EDTA, Propylparaben, Distearyl Dimonium Chloride , Glyceryl Laurate, Potassium Hydroxide, Behentrimonium Methosulfate, Cocamidopropyl PG-Dimonium Chloride Phosphate, Octyldodecanol and PEG- 100 Component or components of stearate.

The concentration of Bacteroides bacteria or cellular components in the compositions of the invention may vary depending on the desired result, the type and form of bacteria or cellular components used, the form and intended method of administration, among other things. For example, compositions of the invention can be prepared having a concentration of bacterial or cellular components in the preparation of not less than about 1 mg to about 1 g by weight, or 1-30X HPUS (Homeopathic Pharmacopoeia of the United States), based on the total weight of the preparation. In one embodiment, the composition may be administered 1, 2, 3 or more times per day. In another embodiment, the composition is administered every 4-6 hours. In yet another embodiment, the composition is administered 1, 2, 3 or more times per week.

Specific examples of suitable compositions contemplated for use in the present invention are provided below.

Example 1

This example demonstrates the preparation of cellular components for use in therapeutic compositions.

Bacterial cell cultures are grown in vats under strictly controlled conditions. Cellular components, such as proteins, obtained from the bacterial cells themselves by lysing the cells, extracting and purifying them, or alternatively from stimulating the bacteria to produce proteins, for example, by varying conditions such as pH, temperature, oxygen, nutrients, or other variables obtained from bacterial cell secretions. Sterile glass Petri dishes/tubes are then inoculated with medium containing lysed cells and/or protein and suspending medium including but not limited to eg up to 10% skim milk with or without 5% sodium tartrate. The material is then eg subjected to centrifugation and washed with a suitable sterile medium (eg suspending medium or buffer solution). Usual additives for freeze-drying may be added, including protectants, stabilizers, buffers, and the like. Fluids are generally removed prior to freeze-drying (lyophilization), which can be performed, for example, at temperatures ranging from about -20°C to about -200°C, more specifically in the range of -50°C to -80°C or lower, typically under vacuum for several hours. Once drying is complete, inert or inactive ingredients, etc., including but not limited to rice flour, magnesium stearate, dicalcium phosphate, cellulose, stearic acid, calcium carbonate and/or silicon dioxide are added to provide a dry powder preparation.

Example 2

This example shows a suitable capsule product.

Using the freeze-drying method, a certain amount of cell components derived from Bacteroides polymorpha cells was prepared in powder form ("active ingredient 1") using the procedure as described in Example 1 .

Table 1

Components 1-4 from Table 1 were mixed for 10 minutes in a suitable mixer. After mixing, 450 mg of the mixture is filled into two gelatin or hypromellose capsules, and the capsules are sealed.

Example 3

This example shows a suitable tablet product.

Using the lyophilization method as described in Example 1, a certain amount of cell components derived from Bacteroides monomorpha cells was prepared in powder form ("active ingredient 2").

Table 2

Components 1-3 from Table 2 were mixed for 10 minutes in a suitable mixer. The mixture is then compressed into 450 mg tablets using a tablet machine.

Example 4

This example shows a suitable suppository product.

A certain amount of cellular components from Bacteroides vulgaris cells was prepared in powder form ("Active Ingredient 3") using the lyophilization method as described in Example 1

table 3

Components 2-4 from Table 3 were charged into a suitable mixer heated to a temperature of 60°C, while stirring at a constant speed, to form a first mixture. Additionally, Component 1 and Component 5 from Table 3 were charged to the mixer and mixed for 10 minutes to form a second mixture. Slowly and while stirring, the second mixture is added to the first mixture, and the resulting mixture is continuously stirred for 10 minutes before being poured into preformed suppository shells. The filled suppository shell is allowed to cool until the suppository sets.

The disclosed compositions of the invention can be administered to a subject to treat, delay the onset and/or reduce the symptoms of inflammation and related diseases. Additionally, the disclosed cellular component compositions can be used to maintain their beneficial effects according to suitable maintenance protocols.

Additionally, in alternative embodiments, existing methods may employ a cleansing step prior to administration of the compositions of the present invention. Alternatively, no bowel cleansing can be used prior to administration. Those skilled in the art will understand that any medically approved diarrhea-inducing chemical can be used as the cleaning chemical/solution for this step. Examples of suitable cleaning chemicals include, without limitation, magnesium citrate, sodium monobasic phosphate (in any form), sodium dihydrogen phosphate in any form, potassium dihydrogen phosphate in any form, and potassium monobasic phosphate in any form. The disclosed compositions of the invention may be administered after the gastrointestinal tract has been cleansed. A suitable dosing regimen of the composition of the present invention may include, for example, administering a certain number of cell component compositions (eg, 3 capsules) with each meal for a certain number of days (eg, 3 days). However, those skilled in the art will understand that the amount and frequency of administration of the disclosed compositions of the invention may depend on the type of bacteria or bacterial cell component being administered, the concentration of the bacteria or cell component in the composition, and the subject. weight, height and/or age, etc. of the patient.

Beneficial effects can be achieved by continuous administration of the disclosed compositions of the invention (eg, 1 capsule per day or 1 capsule per meal) along with a correct maintenance program. For example, subjects may be advised to avoid high-fat and high-sugar foods and focus on consuming certain amounts of fruits and vegetables (eg, two fresh fruits and two servings of vegetables per day). In addition, subjects can be advised to perform at least 3 times per week of 30 minutes of moderate exercise, such as brisk walking. More fresh fruits and vegetables should be encouraged.

To encourage proper use of the disclosed compositions of the invention, the compositions of the invention can be provided with instructions for use and/or suggested cleaning/vaccinating and inoculation protocols and/or protocols that can be customized by the user and used to track progress. Instructions and/or protocols may be provided with the compositions, kits or packs of the invention.

Accordingly, those skilled in the art will appreciate that the disclosed cellular components, compositions of the invention, and related methods can be used to increase exposure to beneficial bacterial species populations or cellular components in the gastrointestinal tract and other systems of the external environment. to assist the anti-inflammatory system without the need for invasive surgery or other drastic techniques. Beneficial bacterial species or cellular components can be maintained with continued administration of the compositions of the invention and optionally with an appropriate maintenance regimen, including appropriate diet and exercise.

The specific embodiments and examples described in this specification are illustrative in nature and do not limit the scope of the invention, which is defined by the claims. While aspects of the disclosed cellular components, compositions and methods of the invention may occur to those skilled in the art upon reading this specification, the invention includes such modifications and is limited only by the scope of the claims.

The following references are incorporated herein and/or may be relevant to one or more aspects discussed in this specification:

Alberti, K.G. and P.Z.Zimmei, 1998. Definition, diagnosis and classification of diabetes mellitus and its complications, part 1: diagnosis and classification of diabetes mellitus, provisional report of a WHO consultation (definition, diagnosis and classification of diabetes mellitus and its complications, part 1 Section: Diagnosis and Classification of Diabetes, WHO Expert Provisional Report). Diab.Med.15:539-553.

Atarashi, K., J Nishimura, T. Shima, Y Umesaki, M. Yamamto, M. Onoue, H. Yagita, N, Ishii, R. Evens, K. Honda and K. Takeda, 2008. ATP drives laminapropria Tgl7 cell differentiation (ATP drives differentiation of Tg ₈ 17 cells in the lamina propria). Nature 455:808-814.

Bals, R., M.J.Goldman and J.M.Wilson, 1998.Mouse beta-defensin 1 is asalt-sensitive antimicrobial peptide present in epithelia of the lung and urigenital tract Salt-sensitive antimicrobial peptides). Infect.and Immun.66(3):1225-1232.

Bjorksten, B, 1999. The environmental influence on childhood asthma (environmental influence on childhood asthma). Allergy.54:17-23.

Brasier, A.R, 2006. The NF-κB regulatory network (NF-κB regulatory network). Cardiovasc. Toxicol.6 (2): 111-130.

Bry, L., P.G.Falk, T.Midvelt and J.L.Gordon, 1996. A model of host-microbial interactions in an open mammalian ecosystem (host-microbial interaction model in an open mammalian ecosystem). Science 273:1380-1383 .

Cerutti, A, 2008. The regulation of IgA production class switching (regulation of IgA production type switching). Nature Rev. Immunol.8:421-434.

Corti, R., R. Flutter, J.J.Badimon, J.J.Badimon and V.Fuster, 2004. Evolving concepts in the triad of atherosclerosis, inflammation and thrombosis (evolving concepts in the three of atherosclerosis, inflammation and thrombosis). J . Thromb. Thromolysis. 17:35-44.

De Winter, H., H. Cheroutre and M. Kronenberg, 1999. Mucosal immunity and inflammation (mucosal immunity and inflammation). II. The yin and yang of T cells in intestinalinflammation: pathogenic and protective roles in a mouse colitis model (intestinal Yin and yang of T cells in inflammation: pathogenic and protective roles in a mouse model of colitis). Am J Physiol. 276:G1317-G1321.

Doyle, S.L. and L.A.O'Neill, 2006. Toll-like receptors: from the discovery of NF-κB to new insights into transcriptional regulations in innate immunity (Toll-like receptors: from the discovery of NF-κB to transcriptional regulation in innate immunity New Understanding). Biochem. Pharmacol. 72(9):1102-1113.

Elson, C.O., Y.Cong, C.T.Weaver, T.R.Schoeb, T.K.McClanahan, R.B.Fick and R.A.Kastelein, 2007. Monoclonal anti-interleukin 23 reverses active colitisin a T cell-mediated model in mice mediates active colitis in a mouse model). Gastroenterology 132:2359-2370.

Frank, D., N.A.L. Amand, R.A. Feldman, E.C. Boedeker and N.R. Pace, 2007. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl. Acad. Sci. USA. 104(34):13780-13785.

Garrett, W.S., G.M.Lord, S.Punit, G.Lugo-Villarino, S.K.Mazmanian, ISusumu, J.N.Glickman and L.H.Gilmscher, 2007. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system Transmissible ulcerative colitis caused by -bet deficiency). Cell.131:33-45.

Gilmore, T.D, 1999. The Rel/NF-κB signal transduction pathway: introduction (Rel/NF-κB signal transduction pathway: Introduction). Oncogene: 18 (49): 6842-6844.

Gilmore, T.D, 2006. Introduction to NF-κB: players, pathways, perspectives (Introduction to NF-κB: role, pathway, perspective). Oncogene: 25 (51): 6680-6684.

Hall, J., N. Bouladoux, C.M. Sun, W.A. Wohlfert, R.B. Blank, Q. Zhu, M.E. Grigg, J.A. Berofsky and Y. Belkaid, 2008.Commensal DNA limits regulatory Tcell conversion and is a natural adjuvant of intestinal immune responses ( Symbiotic DNA restricts regulatory T cell transformation and is a natural adjuvant of the intestinal immune response). 2008. Immunity.29:637-649.

Halpert, I., U.I. Sirest, J.D. Roby, U.I. Sires, S. Potter-Perigo, T.N. Wight, S.D., Shapiro, H.G. Welgus, S.A. Wickliff and W.C. Parks, 1996. Matrilysin isexpressed by lipid-laden macrophages at sites of potential rup in atheroscleroticlesions and localizes to areas of versican deposition, a proteolytic substrate for the enzyme Proteolytic substrates) deposition area). Proc. Natl. Acad. Sci. USA. 93:9748-9753.

He, B., W. Xu, PASantini, AD Polydorides, A. Chiu, J. Estrella, M. Shan, A. Chadburn, M. Shan, A. Chadburn, V. Villanacci, A. Plebani, DM Knowles, M. Rescigo and A. Cerutti, 2007. Intestinal bacteria trigger T cellindependentimmunoglobulin _{A 2 class} switching by inducing epithelial-cell secretion of thecytokine APRIL . Immunity 26:812-826.

Henderson, B., S. Poole and M. Wilson, 1996. Bacterial modulins: a novel class of virulence factors which cause host tissue pathology by inducing cytokinesynthesis Force Factor) Microbiol.Rev.60(2):316-341.

Hooper, L.V., M.H.Wong, A.Thelin, L.Hansson, P.G.Falk and J.1.Gordon, 2001. Molecular analysis of commensal host-microbial relationships in the intestine (molecular analysis of commensal host-microbial relationships in the intestine). Science 291:881-884.

Hotamisligil, G.S, 2006. Inflammation and metabolic disorders (inflammation and metabolic disorders) Nature.444:860-867.

Hu, F.B., J.E.Manson, M.J.Stamper, G.Colditz, S.Lui, C.G.Soloman, and W.C.Willet, 2001. Diet, Lifestyle and the risk of type 2 diabetes mellitus in women Diabetes Risk). New Engl. J. Med. 345(11):790-797.

Hultgren, S.J, S.Abraham, M.Caparon, P.Faulk, J.W.St.Gerne III and S.Numark, 1993.Pilus and nonpilus bacterial adhesins: assembly and function in celladhesion (pilus and nonpilus bacterial adhesion Proteins: assembly and function in cell adhesion). Cell. 73:887-901.

Ivonav, 1.1., R. deLlanos Frutos, N. Manel, K. Yoshinaga, D.B. Rifkin, B. Brett Finlay and D.R. Littman, 2008. Specific microbiota direct differentiation of IL-17-producing T-helper cells in the mucosa of the small Intestine (Specific microbiota direct differentiation of IL-17-producing helper T cells in the small intestinal mucosa). Cell Host Microbe 4:337-349.

Kalliomaki, M. and E. Isolauri, 2002. Pandemic of atopic diseases-a lack of microbial exposure in early infancy? (Pandemic atopic disease-lack of microbial exposure in early infancy?) Curr. Drug Targets Infect. Disord.2: 193-199.

Kalliomaki, M. and E. Isolauri, 2003. Role of the intestinal flora in the development of allergy. Curr. Opin. Allergy Clin. Immunol. 3:15-20.

Kojima, S., T. Funshashi, H. Maryoshi, O. Honda, S. Sugiyama, H. Kawano, H. Soejima, S. Miyamoto, J. Hokamaki, T. Sakamoto, M. Yoshimura, A. Kitagawa, Y Matsuzawa and H.Ogawa, 2005. Levels of the adipocyte-derived plasma protein, adiponectin, have a close relationship with atheroma (the level of adipocyte-derived plasma protein - adiponectin - has a close relationship with atheroma).Thromb.Res .115:483-490.

Lepage, P., P. Seksik, M. Sutren, M.-F. de la Cochetiere, R. Jian, P. Mateua and J. Dore, 2005. Biodiversity of the mucosa-associated microbiota is stable along thedistal digestive tract in healthy individuals and patients with IBD (Biodiversity of mucosa-associated microbiota is stable along the distal alimentary tract in healthy individuals and patients with IBD). Inflamm. Bowel Dis. 11:473-480.

Lin, W-W. and M. Karin, 2007. A cytokine-mediated link between innateimmunity, inflammation, and cancer (cytokine-mediated link between innate immunity, inflammation, and cancer). J. Clin. Invest. 117 (5) :1175-1183.

Lopez-Baodo, Y.S., C.L.Wilson, L.V.Hooper, J.I.Gordon, S.J.Hultgren, and W.C.Parks, 2000. Bacterial Exposure induces and activates matrilysin inmucosal epithelial cells. J. Cell. . Biol. 148(6):1305-1315.

Lupton, J.R, 2004. Microbial degradation products influence colon cancer risk: the butyrate controversy. J. Nutr. 134:479-482.

Macpherson, A.J. and T.Urh, 2004. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria (Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria). Science:303:1662-1665.

Mazmanian, S.K., C.H.Lui, A.O.Tzianabos and D.Kasper, 2005. Animmunomodulatory molecule of symbiotic bacteria directs maturation of the hostimmune system (commensal bacteria immunomodulatory molecule guides the maturation of the host immune system). Cell.122:107-118.

Mazmanian, S.K., J.L.Round and D.Kasper, 2008. A microbial symbiosis factor prevents intestinal inflammatory disease (microbial symbiosis factor prevents intestinal inflammatory disease). Nature.453:620-625.

Murphy, G., M.I.Cockett, R.V.Ward and A.J.P.Docherty, 1991. Matrix metaloproteinase degradation of elastin, type IV collegan and proteoglycan. Aquantitative comparison of the activities of 95 kDa and 78 kDa gelatin and pulatinase ed opylesins-1 (PUMP) (matrix metalloprotease degradation of elastin, collagen type IV, and proteoglycans: quantitative comparison of the activities of 95 kDa and 78 kDa gelatinases, stromelysin-1 and -2, and truncated metalloproteinases (PUMPs)). Biochem. J. 277:277-279.

Muta, T and K. Takeshige, 2001. Essential roles of CD 14 andlipopolysaccharide-binding protein for activation of toll-like receptor (TLR) 2aswellas TLR4: Reconstitution of TLR2-and TLR4-activation by distinguished ligands in LPS 1 preparations Key roles of polysaccharide-binding proteins in activating toll-like receptor (TLR) 2 as well as TLR4: reconstitution of TLR2-activated and TLR4-activated by ligands differentiated in LPS preparations). Eur. J. Biochem. 268(16): 4580- 4589.

Nelson, D.E, A.E. Hiekwaba, E.M. Johnson, C.A. Gibney, B.E. Foreman, G. Nelson, S Vee, C.A. Horton, D.G. Spiller, S.W. Edwards, H.P. McDowell, J.F., J.F. Unitt, S.E. Sullivan, R. Grimley, N. Benson , D.Broomhead, D.B.Kell and M.R.White, 2004.Oscillations in NF-κB signaling control the dynamics of gene expression (dynamics of NF-κ1B signal transduction control gene expression).Science.306(5696):704- 708.

Noverr, M.C. and G.B. Huffnagie, 2004. Does the microbiota regulate immune responses outside the gut? (Does the microbiota regulate immune responses outside the gut?). Trends Microbial. 12:562-568.

Ouettlette, A.J., M.M. Hsieh, M.T. Nosek, D.F. Cano-Gauci, K.M. Huttner, R.N. Buick, and S.E. Selsted, 1994. Mouse Paneth cell defenses: primary structures and antibacterial activities of numerous cryptdin isoforms Primary structure and antibacterial activity of numerous crypt defense peptide (cryptdin) isoforms). Infect. Immun. 62:5040-5047.

Ouellette, A.J. and S.E.Selsted, 1996. Paneth cell defensins: endogenouspeptide components of intestinal cell defense (Paneth cell defensins: endogenous peptide components of intestinal cell defense). FASEB J. (Fed.Am.Soc.Exp . Biol. J.). 10:1280-1289.

Penders, J., C. Thijs, P.A. van den Brandt, I. Kummeling, B. Snijders, F. Stelma, H. Adams, R. von Ree and E.E. Stobberingh, 2007. Gut microbiotacomposition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study (Gut microbiota composition and development of heterotopia in infants: A KOALA Birth Cohort Study). Gut.56:661-667.

Peterson, D.A., N.P. McNutty, J.L. Guruge, and J.I. Gordon, 2007. IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2:328-339 .

Podolsky, D.K, 2002. The current future understanding of inflammatory bowel disease. Best Pract. Res. Clin. Gastroenterol. 16:933-943.

Rakoff-Nahoum, S., J.Paglino, F.Eslami-Varzaneh, S.Edberg and R.Medzhitov, 2004. Recognition of commensal bacteria by Toll-like receptors is required for intestinal homeoastasis (commensal bacteria are recognized by Toll-like receptors is Intestinal homeostasis). Cell 118:229-241.

Ryo, M., T. Nakamura, S. Kihara, M. Kumada, S. Shibazaki, M. Takhashi, M. Nagai, Y. Matzuzawa and T. Funahashi, 2004. Adiponectin as a biomarker of the metabolic syndrome (adiponectin as a biomarker for the metabolic syndrome). Circ. 7.68:975-981.

Saarialho-Kere, U.K., H.G. Welgus and W.C. Parks, 1993. Divergent mechanisms regulate interstitial collagenase and 92 kDa gelatinase expression in human monocyte-like cells exposed to bacterial endotoxin (Divergent mechanisms regulate in human monocyte-like cells exposed to bacterial endotoxin Expression of Interstitial Collagenase and 92 kDa Collagenase). J. Biol, Chem. (268): 17354-17361.

Scanlan, P.D., F. Shanahan, C.O Mahony, and J.R. Marchesi, 2006. Culture-independent analyzes of temporal variation of the dominant fecalmicrobiota and targeted bacterial subgroups in Crohn's disease Temporal variation in directed bacterial subgroups). J. Clin. Microbiol. 44:3980-3088.

Shanahan, F, 2002. Crohn's Disease. Lancet. 359:62-69.

Shoelson, S.E., J.Lee, and A.B. Goldfine, 2006. Inflammation and insulin resistance. J. Clin. Invest. 116:1793-1801.

Simpson, S.J., Y.P.de Jong, M.Comiskey, C.Terhorst, 2000.Pathways of Tcell pathology in models of chronic intestinal inflammation (pathway of T cell pathology in chronic intestinal inflammation model).Int.Rev.Immunol.19: 1-37.

Sires, U.I., G.L.Griffin, T.Broekelman, R.P.Mecham, G.Murphy, A.E.Chung, H.G.Welgus and R.M.Senior, 1993.Degradation of entactin by matrixmetaloproteinases.Susceptibility to matrylisin and identification of cleavage sites Proteins: susceptibility to matrylisin and identification of cleavage sites). J. Biol. Chem. 26S:2069-2074.

Skurk, T. and H. Hauner, 2004. Obesity and impaired fibrinolysis: role ofadipose production of plasminogen activator-1 (Obesity and impaired fibrinolysis: plasminogen activator-1 of fat production role). Int. J. Obes. 28:1357-1364.

Solinas, G, C. Vilcu, J.G. Neels, G.K. Banyopadhiyay, J-L Luo, W. Naugler, S. Grivnenikov, A. Wynshaw-boris, M. Scadeng, J.M. Olefsky and M. Karin, 2007. JNK1 in hematopoetically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity (JNK1 in hematopoietic derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity). Cell Metabol.6:386-397.

Suzuki, K., B. Meek, Y. Doi, M. Muramatsu, T. Chiba, T. Honjo, and S. Fagarasan, 2004. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut (segmented in IgA-deficient gut Abnormal expansion of filamentous bacteria). Proc. Natl. Acad. Sci. 101:1981-1986.

Targan, S.R. and L.C. Karp, 2005. Defects in mucosal immunity leading toulcerative colitis. Immunol. Rev. 206:296-305.

Tezuka, H., Y. Abe, M. Iwata, H. Takeuchi, H. Ishikawa, M. Matsushita, T. Shiohara, S. Akira and T. Ohteki, 2007, Regulation of IgA production by naturally occurring TNF/iNOS-producing Dendritic cells (regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells). Nature 448:929-933.

White, C.R, 2003. Insulin signaling in health and disease (insulin signaling in health and disease). Science.302:1710-1711.

Wilson, C.L., A.J. Ouellette, D.P. Satchell, T. Ayube, Y.S. Lopez-Boada, J.L, Stratman, S.J. Hultgren, L.M. Matrisian, and W.C. Parks, 1999. Regulation of testinal alpha-defensin activation by the metalloproteinase defensin host in finnate (natural host Regulation of intestinal alpha-defensin activation by metalloproteinases in defense). Science. 286: (113-123).

Wilson, M.R. Seymour and B. Henderson, 1998. Bacterial perturbation of cytokine networks. Infect. Immun. 66:2401-2409.

Zaneveld, J., P.J.Turnbaugh, C.Laozupone, R.E.Ley, M.Hamady, J.I.Gordon and R.Knight, 2008.Host-bacterial coevolution and the search for new drug targets (host-bacteria coevolution and exploration of new drug targets ). Curr. Opin. Chem. Biol. 12:109-114.

Claims (22)

1. a cracking from the bacterium that is derived from Bacteroides (Bacteroides), by its generation and/or from the cellular component that wherein separates or the derivative of described cellular component.

2. cellular component according to claim 1 or derivative, wherein, described cellular component comes from bacterium, and described bacterium is selected from bacteroides thetaiotaomicron (Bacteroides thetaiotaomicron), bacteroides fragilis (B.fragilis), bacteroides vulgatus (B.vulgatis), bacteroides distasonis (B.distasonis), bacteroides ovatus (B.ovatus), Bacteroides merdae (B.merdae), bacteroides uniformis (B.uniformis), bacteroides eggerthii (B.eggerithii) and excrement bacterioide (B.caccae).

3. cellular component according to claim 1 or derivative comprise DNA or RNA.

4. cellular component according to claim 1 or derivative comprise the cell-wall component that is selected from lipopolysaccharides, lipid, sugar, protein, lipoprotein, glycoprotein and combination thereof.

5. cellular component according to claim 1 or derivative comprise the product of bacterium and are selected from lipid, sugar, protein and genetic material.

6. Foods or drinks, it is supplemented with according to claim 1 each described cellular component or derivatives thereof in-5.

7. the composition that is used for oral administration comprises according to claim 1 in-5 acceptable carrier on each described cellular component or derivatives thereof and physiology.

8. composition according to claim 7, wherein, described carrier is selected from capsule shell, film-making agent and polymeric matrix.

9. composition according to claim 7, wherein, described carrier is selected from capsule shell, film-making agent, polymeric matrix and the component of prolongation release, delayed release or the sustained release of described cellular component or derivatives thereof is provided.

Health or gastrointestinal tract inflammation in the treatment individuality, postpone its outbreak or reduce the method for its symptom, comprise administration comprise the Bacteroides bacterium or according to claim 1-5 in the composition of each described cellular component or derivatives thereof.

11. be used for the treatment of individual central vessel disease, postpone its outbreak or reduce the method for its symptom, comprise administration comprise the Bacteroides bacterium or according to claim 1-5 in the composition of each described cellular component or derivatives thereof.

12. be used for the treatment of diabetes in the individuality, postpone its outbreak or reduce the method for its symptom, comprise administration comprise the Bacteroides bacterium or according to claim 1-5 in the composition of each described cellular component or derivatives thereof.

13. be used for the treatment of colorectal carcinoma in the individuality, postpone its outbreak or reduce the method for its symptom, comprise administration comprise the Bacteroides bacterium or according to claim 1-5 in the composition of each described cellular component or derivatives thereof.

14. be used for the treatment of gastrointestinal tract inflammation in the individuality, postpone its outbreak or reduce the method for its symptom, comprise administration comprise the Bacteroides bacterium or according to claim 1-5 in the composition of each described cellular component or derivatives thereof.

15. method according to claim 14, wherein, described gastrointestinal tract inflammation and the disease-related that is selected from irritable bowel syndrome, Crohn's disease and colitis.

16. be used for the treatment of rheumatoid arthritis in the individuality, postpone its outbreak or reduce the method for its symptom, comprise administration comprise the Bacteroides bacterium or according to claim 1-5 in the composition of each described cellular component or derivatives thereof.

17. be used for the treatment of asthma in the individuality, postpone its outbreak or reduce the method for its symptom, comprise administration comprise the Bacteroides bacterium or according to claim 1-5 in the composition of each described cellular component or derivatives thereof.

18. be used for the treatment of multiple sclerosis in the individuality, postpone its outbreak or reduce the method for its symptom, comprise administration comprise the Bacteroides bacterium or according to claim 1-5 in each described cellular component.

19. each described method according to claim 10-18, wherein, the administration in Foods or drinks of described composition.

20. bacterium from the genetic modification of Bacteroides.

21. be used for the composition of oral administration, comprise acceptable carrier on the bacterium of genetic modification according to claim 20 and the physiology.

22. a synthetic molecule of deriving, it is based on from the molecule/molecular pattern in the species of Bacteroides inside.